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Pharmacokinetics > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

What is drug distribution?

A

The post absorptive transfer of drug from one location in the body to another

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2
Q

Why is one compartment model not adequate to describe drug distribution?

A

Because drug distribution would be assumed to occur instantaneously at time = 0

Therefore multi compartmental models are required to describe drug distribution

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3
Q

What are the two components of drug distribution?

A

Rate and extent of distribution

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4
Q

What can estimate the rate of drug transfer between compartments?

A

Distribution clearance (CLd)

Also known as inter compartmental clearance or rate of perfusion (Q)

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5
Q

What does volume of distribution assess?

A

The extent of drug distribution

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6
Q

What are the two steps of distribution?

A

Presentation of the drug to the tissue by the blood
Diffusion or uptake of drug from the blood to the tissue

The rate of distribution is limited by the slower of these steps

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7
Q

What does hydrostatic pressure do for movement of the drug?

A

Creates the pressure gradient between the arterial end entering the tissue and the venous capillaries leaving the tissue

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8
Q

What is hydrostatic pressure responsible for?

A

Penetration of water soluble drugs into spaces between endothelial cells and maybe into the lymph

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9
Q

What is the rate of tissue perfusion?

A

Q
The rate of drug presentation to the tissues

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10
Q

What is the unit of tissue perfusion?

A

Described by the volume of blood delivered to the tissue per unit time

mL/min

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11
Q

TF: The rate of drug presentation to different tissues will vary from one to another based on the rate of tissue perfusion.

A

True

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12
Q

What happens to drug distribution to patients with congestive heart failure?

A

In perfusion controlled drugs, there will be an accumulation of drug in the body and an increase in toxicity, so the dose would need to be lowered

There would be a decrease in perfusion rate

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13
Q

What happens once the drug molecule arrives close to tissue site?

A

They rapidly diffuse into interstitial fluid of capillaries and further diffuse from the IF across the tissue membrane to be in the tissue, driven by the passive diffusion across the epithelial membrane

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14
Q

What kind of drugs are diffusion controlled?

A

Polar molecules (cannot pass through membrane readily)

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15
Q

What kind of drugs are perfusion controlled?

A

Non polar molecules

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16
Q

What happens to permeability of capillaries and cells when inflammation occurs?

A

It increases which allows polar molecules to pass through the membrane

Diffusion controlled
Permeability controlled

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17
Q

What does distribution half life represent?

A

Represents the time required for the plasma concentration to decline by 50% during the distribution phase

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18
Q

What is distribution half life used to determine?

A

How long a drug takes to distribute from central to peripheral compartment

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19
Q

In Cp=Ae-at+Be-Bt what does a represent?

A

The distribution of rate constant

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20
Q

How do you find t1/2 in two compartment model?

A

t1/2, alpha= 0.693/alpha

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21
Q

How do you find time to reach steady state in distribution?

A

tss=(t1/2,alpha)*5

When rate in = rate out

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22
Q

What is the extent of drug distribution?

A

The relative distribution of drug molecules between blasma and the rest of the body

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23
Q

What is the rate of distribution?

A

How fast the drug distribution takes place

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24
Q

What is the normal volume of plasma for an average healthy adult?

A

3L

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25
Q

What volume is in an average healthy adult of blood?

A

5L

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26
Q

What are the three physiological fluid volumes in which drugs distribute?

A

Plasma (3L)
Extracellular fluid (15L)
Total body fluid (42L)

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27
Q

How much interstitial water is in an average healthy adult?

A

12L

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28
Q

How much intracellular water is found in an average healthy adult?

A

27L

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29
Q

Where do the drug molecules distribute throughout after absorption, once the drug molecules are in systemic circulation?

A

Throughout the volume of plasma water

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30
Q

What happens to movement of drug when lipid solubility is increased?

A

Favoring drug movement OUTSIDE plasma

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31
Q

What happens to drug movement amount when molecular size is decreased?

A

Favoring movement of drug outside the plasma

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32
Q

What happens to drug movement when plasma protein binding is increased?

A

Restricts movement of drug outside plasma

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33
Q

What are the factors that determine the extent of drug distribution beyond plasma water?

A

Physiochemical properties of the drug
Permeability characteristics of the membrane

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34
Q

IF the drug is distributed only in the plasma what is the approximate Vd in an average person?

A

0.04 L/Kg

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35
Q

What kind of drugs would you want a drug limited to plasma distribution?

A

Anticoagulant, anemia

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36
Q

What are most drugs distributed throughout?

A

the volume of extracellular fluid (15L)

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37
Q

Why are most drugs distributed through the volume of extracellular fluid?

A

Because epithelial membrane of the capillary cells is very loose and permits passage of even polar and protein molecules

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38
Q

What is included in extracellular fluid?

A

Plasma and interstial water

39
Q

What is the Vd in an average person for drugs that distribute in the extracellular fluid?

A

0.2L/Kg

40
Q

What does a drugs’ ability to penetrate individual cell membrane depend on?

A

Physicochemical properties

Small lipophilic drugs penetrate biological membranes easily and distribute throughoutt the total body water (unless specialized uptake transporters then polar molecules and larger molecules can pass)

40
Q

What does a drugs’ ability to penetrate individual cell membrane depend on?

A

Physicochemical properties

Small lipophilic drugs penetrate biological membranes easily and distribute throughoutt the total body water (unless specialized uptake transporters then polar molecules and larger molecules can pass)

41
Q

What is the approximate Vd ina an average person for a drug that distribures in total body water?

A

0.6 L/Kg

42
Q

What kind of drugs would go beyond total body fluid?

A

Highly lipophilic and with high tissue structure binding affinities
Very small molecular weight

43
Q

TF: In reality the extent of volume distribution of many drugs is equal to the total body fluid?

A

False most are greater than the total body fluid

In addition to the available physiological volumes, drugs’ properties drive the extent of the drugs distribution

44
Q

What kind of drugs are antibiotics for IV?

A

Aminoglycosides
Highly polar drugs

45
Q

What is apparent volume of distribution?

A

The extent of drug distribution

46
Q

What is Vd?

A

Hypothetical volume of fluid required to contain the total dose of a drug in the body at the same concentration as that present or measured in the plasma

47
Q

How do you find Vd?

A

Vd= Amount of drug in the body/ Concentration in plasma

48
Q

What is Vd affected by?

A

pathological conditions that disturb either body volumes (dehydration), plasma protein concentrations and binding, or tissue binding

49
Q

What is Vd affected by?

A

pathological conditions that disturb either body volumes (dehydration), plasma protein concentrations and binding, or tissue binding

50
Q

True false
Vd varies with body weight

A

True

51
Q

What do we use to estimate the apparent Vd

A

Compartmental PK models are utilized best

52
Q

True False: Vd is not constant for a drug

A

False
Vd is constant for a drug

Assuming normal physiologic and health conditions

53
Q

True False: Vd is not constant for a drug

A

False
Vd is constant for a drug

Assuming normal physiologic and health conditions

54
Q

How many different volumes of distribution are shown in plasma concentration time curve of drugs that display two or multi-compartment distribution models?

A

three

Characterized based on the time they occur after the dose

55
Q

Why is Vss clinically important?

A

Because of physiological relevance reflecting the extent of drug distribution from the plasma pool into tissues

56
Q

What are the two approaches for estimating Vss?

A

Based on 2 compartment system (Vc+VB)
Based on the extent of drug binding to plasma proteins with the actual plasma volume and the extent of drug binding to tissue proteins with the actual tissue volumes

57
Q

At equilibrium between the plasma and tissues the extent of drug distribution depends on….?

A

It binding to plasma proteins
Blood cells
tissue structures
Actual total volumes of plasma and tissues

58
Q

True False
Drug binding to plasma proteins and tissue structures have very important influence of drug distribution

A

True

59
Q

How could Vd exceed physiological total body volume?

A

Because drug binding to peripheral tissue structures

60
Q

What are the plasma proteins that could bind to drug molecules?

A

Albumin
Globulins
Alpha 1 acid glycoproteins
lipoproteins

61
Q

What are the tissue structures that could bind to drug molecules?

A

Nucleic acids
Ligands
Calcified tissues
Adenosine triphosphate

62
Q

What kind of drug can diffuse outside the plasma and participate in the concentration gradient that drives the distribution process?

A

Unbound or free portion of drug

Bound drugs cannot participate

63
Q

Where is albumin synthesized?

A

In the liver
55% plasma proteins

64
Q

A drug with 90% plasma protein binding but does not bind to tissue structures is how much unbound?

A

10%

65
Q

What is the relationship between free concentrations of drug in the plasma and bound concentrations of drug in the tissues at steady state?

A

They are equal

66
Q

At steady state what is the relationship between total concentration of drug in plasma compared to tissue in drugs that have high plasma protein binding?

A

Total concentration of drug (bound and unbound) i the plasma&raquo_space;»» Total concentration of drug (bound and unbound) in the tissue

67
Q

What restricts the distribution of drug outside of plasma while concentrating it in the plasma?

A

The strength of plasma protein binding

Causes Vd to be smaller values

68
Q

What is the relationship between volume of distribution and half life?

A

The greater the volume of distribution the greater the half life

69
Q

How do you find amount in the body?

A

A=Vd*Cplasma

70
Q

Bd,ss=Vplasma+Vtissue*((fu,plasma/fu,tissue))

A

KNOW THIS

71
Q

How do you find unbound plasma concentration?

A

=Cplasma*fu,plasma

72
Q

How do you find unbound tissue concentration?

A

Ctissue*fu,tissue

73
Q

In the plasma, drug exists in what 2 forms?

A

Unbound and bound forms

74
Q

How does binding occur?

A

Very rapidly and completley reversible

75
Q

How does equilibrium between the unbound and bound forms establish?

A

Quickly

If the unbound drug concentration decreases, bound drug dissociates rapidly to restore equilibrium

76
Q

What is the clinically measured concentration?

A

Unbound and bound concentration

77
Q

What is the equilibrium of unbound and bound drug?

A

Drug unbound + plasma protein total = Drug plasma protein complex bound

78
Q

What does the unbound free drug concentration do?

A

Diffuses across membranes to the drug’s site of action
Interacts with the receptors to cause pharmacological and toxicological activities
Available for distribution and elimination

79
Q

How can the unbound plasma drug concentrations be calculated?

A

Cp,u=Cp*fu,p

80
Q

What is affinity?

A

The magnitude of the association constant

k1/k2

81
Q

When does affinity increase?

A

K1»»»k2,
the ratio increases and drug binding to plasma protein is favored , the drug binds to plasma proteins extensively

k1/k2

82
Q

When plasma protein binding increases in proportion to increase in drug concentrations, what happens to fu?

A

Remains constant over therapeutic plasma concentrations with a few exception drugs

83
Q

When would albumin decrease in concentration?

A

Liver disease, age, pregnancy, burns, other trauma

Lower plasma proteins and more free drug

84
Q

When would albumin synthesis increase?

A

Thyroid hormone
Corticosteroids
Growth hormone
Insulin

Increase in plasma proteins and binding

85
Q

What kind of drugs bind to albumin?

A

Acidic

Glycoproteins are basic

86
Q

When would AAG concentrations increase?

A

Physiological stress
(MI)
Cancer
Surgery

Increase binding

87
Q

When would lipoproteins decrease in concentration?

A

Dieting and therapy with statins

88
Q

When would lipoproteins increase in concentrations?

A

Alcoholism
Diabetes mellitus

Increase in binding

89
Q

What would happen if you gave warfarin and asprin?

A

Asprin would replace warfarin in binding and would increase free warfarin which would increase toxicity

Binding of one drug may displace a second drug from its binding site(concentration dependent displacement)

90
Q

What two factors cause a minimization clinical consequences of changes in plasma protein binding?

A

Increased elimination
Little change in drug concentrations outside the plasma

91
Q

How does increase elimination decrease clinical consequences of changes in plasma protein binding?

A

Unbound drug is accessible to the elimination organs

WHen protein binding decreases, unbound drug concentration increases, proportional increase in elimination, eventually the unbound drug concentration in the plasma decreases to same value as that before the change in binding

Increase in unbound concentration is canceled out by increased elimination

92
Q

How do you find loading dose?

A

LD=Vs*TargetCp

Pharmacokinetics (2 decks)

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